Omega-3 fatty acids (n-3FA) may have a role both in primary and secondary prevention of coronary artery disease (CAD). Their protective effects are partially attributed their lipid lowering properties. n-3FA consistently lower the plasma triglycerides (TG). However their effects on low (LDL) and high density (HDL) lipoproteins are variable. We observed that in some patients with type II diabetes mellitus (DM), n-3FA fail to improve plasma LDL or HDL and even raise the plasma protein (apo) B, suggesting an increase in the number of LDL particles. Our work in Zucker rats, an insulin resistant obese and hypertriglyceridemic model, suggested that n- 3FA lower the TG by suppressing the hepatic lipogenic enzymes. Our work lead us to postulate that of n-3FA suppress hepatic lipogenic enzymes. This causes a reduction in the TG in very low density lipoproteins (VLDL) and an associated decrease in their particle size; which , together with a concurrent increase in lipoprotein lipase (LPL) activity, expedites the conversion of VlDL to LDL. However, any resultant increase in plasma LDL is more likely to occur in subjects with an abnormal pre-treatment lipid profile or an abnormal apoE phenotype. n-3FA also replace the fatty acids (FA) in VLDL an d alter lipolytic properties. Type II diabetics are more susceptible to the effects of n-3FA, since they have increased VLDL production and some decrease in their LPL reserve. We plan to challenge these hypothesis in four groups of type II diabetics, categorized on the basis of their plasma lipids (normal, types IIa, IIb, IV/V hyperlipidemias). We shall measure the TG content, Fa composition and particle size of VLDL, LPL activity and the rate of in vivo and in vitro lipolysis of VLDL into LDL before, during and after 12 wks treatment with n-3FA. The responses observed will be correlated with patients' pre- treatment lipid profiles and lipid profiles and apoE phenotypes. The results obtained in diabetics will be compared to those obtained in age, sex and weight matched non-diabetic controls. Type II DM associated with a two to three-fold increase in CAD. The unfavorable lipid response we have observed in some subjects is not limited to n-3FA therapy but can occur in response to fibric acid derivatives, insulin or weight loss. Our study should provide information which can improve the clinical management of type II DM.